Chronic reduction in uteroplacental blood flow which results in reduction substrate and oxygen supply to the fetus produces asymmetric growth retardation. The objective of proposal 6B is to determine the time-course of the fetal metabolic and growth factor responses to chronic reductions in uteroplacental blood flow from day 110 to 138 of gestation. We propose that changes in intermediary metabolism and/or growth factor synthesis and release occur when uteroplacental blood flow is chronically reduced and are responsible for alterations in fetal growth and development. In the present proposal we will determine effects of prolonged reductions in uteroplacental blood flow (day 110 to 138 of gestation) on oxygen and substrate delivery and utilization by the uteroplacental blood flow. Crown-rump length will also be measured daily as an index of fetal growth. Upon documentation of the deficient nutrient in animals exposed to reduced uteroplacental blood flow we will determine the effects of direct fetal supplementation. We will determine if nutrient supplementation via the umbilical vein alters placental production of ovine placental lactogen and IGF's, fetal insulin, and fetal IGF-I and IGF-II concentrations. In the final series of studies, we will evaluate the effects of the combination of increased uteroplacental oxygen delivery and direct fetal supplementation with nutrient(s) on growth in fetuses exposed to reduced uteroplacental blood flow. We will determine if nutrient supplementation in the presence of increased uteroplacental oxygen delivery alters ovine placental lactogen and placental IGF, fetal insulin, and fetal IGF-I and IGF-II concentrations. On day 138 of gestation, all experimental animals will be sacrificed, and fetal and placental morphometric measurements will be made. The studies described above will be performed in a well-developed animal model of reduced uteroplacental blood flow which produces asymmetric growth retardation. These studies will provide us with new insight into fetal adaptation to chronic reductions in uteroplacental blood flow.